The objectives of this project are: To determine the nature of the antigenic determinants on the hemagglutinin (HA) and neuraminidase (NA) molecules of influenza viruses and the molecular mechanism of antigenic drift. Our main approach will be to sequence HA molecules (and the corresponding RNA segments) of influenza virus variants occurring naturally of selected under antibody pressure. In order to monitor drift in single antigenic determinants, we will use variants selected with monoclonal antibodies. This should enable us to find out: (a) What are the exact changes which occur in the amino acid sequence of the HA polypeptides of different variants selected with the same clone of antibody and of variants selected with different clones. (b) Whether the changes in amino acid sequence occur within the antigenic sites or whether they occur somewhere else in the HA molecule and alter the determinants through conformational changes. Similar experiments will be done with NA, using naturally occurring antigenic variants. We will try to isolate antigenic fragments of the HA molecule. We will also make derivatives of amino acid side chains exposed on the surface of the HA and see if these interfere in antibody binding, and make derivatives of the HA to which antibody molecules are bound, to see if antibody "protects" any amino acid side chains.